WO2012062748A1 - Aminoalcohol substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis - Google Patents
Aminoalcohol substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis Download PDFInfo
- Publication number
- WO2012062748A1 WO2012062748A1 PCT/EP2011/069637 EP2011069637W WO2012062748A1 WO 2012062748 A1 WO2012062748 A1 WO 2012062748A1 EP 2011069637 W EP2011069637 W EP 2011069637W WO 2012062748 A1 WO2012062748 A1 WO 2012062748A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- methoxy
- dihydroimidazo
- quinazolin
- carboxamide
- Prior art date
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 53
- 201000010099 disease Diseases 0.000 title claims abstract description 30
- 230000033115 angiogenesis Effects 0.000 title abstract description 10
- 230000003463 hyperproliferative effect Effects 0.000 title abstract description 8
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- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims description 36
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 125000005455 trithianyl group Chemical group 0.000 description 1
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- KIGCDEJCMKDBHU-NIQQUOCOSA-K ukrain Chemical compound [OH-].[OH-].[OH-].C([C@H](O)[C@@H]1C2=CC=C3OCOC3=C2C2)C3=CC=4OCOC=4C=C3[C@H]1[N+]2(C)CCNP(=S)(NCC[N+]1(C)[C@@H]2C3=CC=4OCOC=4C=C3C[C@H](O)[C@@H]2C2=CC=C3OCOC3=C2C1)NCC[N+]1(C)[C@@H]2C3=CC(OCO4)=C4C=C3C[C@H](O)[C@@H]2C2=CC=C3OCOC3=C2C1 KIGCDEJCMKDBHU-NIQQUOCOSA-K 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- AUFUWRKPQLGTGF-FMKGYKFTSA-N uridine triacetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)NC(=O)C=C1 AUFUWRKPQLGTGF-FMKGYKFTSA-N 0.000 description 1
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- 229950010938 valspodar Drugs 0.000 description 1
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- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
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- 235000012141 vanillin Nutrition 0.000 description 1
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- 235000013311 vegetables Nutrition 0.000 description 1
- 229960003862 vemurafenib Drugs 0.000 description 1
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 1
- 229960003895 verteporfin Drugs 0.000 description 1
- ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N verteporfin Chemical compound C=1C([C@@]2([C@H](C(=O)OC)C(=CC=C22)C(=O)OC)C)=NC2=CC(C(=C2C=C)C)=NC2=CC(C(=C2CCC(O)=O)C)=NC2=CC2=NC=1C(C)=C2CCC(=O)OC ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N 0.000 description 1
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- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
- 229960001771 vorozole Drugs 0.000 description 1
- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 1
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- QDLHCMPXEPAAMD-QAIWCSMKSA-N wortmannin Chemical compound C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O QDLHCMPXEPAAMD-QAIWCSMKSA-N 0.000 description 1
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- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 229950008250 zalutumumab Drugs 0.000 description 1
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- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 description 1
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- CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 description 1
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5386—1,4-Oxazines, e.g. morpholine spiro-condensed or forming part of bridged ring systems
-
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
Definitions
- the present invention relates to arylaminoalcohol-substituted 2,3- dihydroimidazo[1 ,2-c]quinolines, (hereinafter referred to as "compounds of general formula (I)”) as described and defined herein, to methods of preparing said compounds, to intermediates for the preparation of said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of a hyper- proliferative and/or angiogenesis disorder, as a sole agent or in combination with other active ingredients.
- compounds of general formula (I) arylaminoalcohol-substituted 2,3- dihydroimidazo[1 ,2-c]quinolines
- lipid kinases In addition to the actions of protein kinases, lipid kinases also play an important role in generating critical regulatory second messengers.
- the PI3K family of lipid kinases generates 3'- phosphoinositides that bind to and activate a variety of cellular targets, initiating a wide range of signal transduction cascades (Vanhaesebroeck et al., 2001 ; Toker, 2002; Pendaries et al., 2003; Downes et al., 2005). These cascades ultimately induce changes in multiple cellular processes, including cell proliferation, cell survival, differentiation, vesicle trafficking, migration, and chemotaxis.
- PI3Ks can be divided into three distinct classes based upon differences in both structure, and substrate preference. While members of the Class II family of PI3Ks have been implicated in the regulation of tumor growth (Brown & Shepherd, 2001 ; Traer et al., 2006), the bulk of research has focused on the Class I enzymes and their role in cancer (Stauffer et al., 2005; Stephens et al., 2005; Vivanco & Sawyers, 2002; Workman, 2004; Chen et ai, 2005; Hennessy et ai, 2005; Cully et ai, 2006). Class I PI3Ks have traditionally been divided into two distinct sub-classes based upon differences in protein subunit composition.
- the Class l A PI3Ks are comprised of a catalytic p110 catalytic subunit (pi 10a, ⁇ or ⁇ ) heterodimerized with a member of the p85 regulatory subunit family.
- the Class l B PI3K catalytic subunit ( ⁇ ⁇ ) heterodimerizes with a distinct p101 regulatory subunit (reviewed by Vanhaesebroeck & Waterfield, 1999; Funaki et al., 2000; Katso et al., 2001).
- the C-terminal region of these proteins contains a catalytic domain that possesses distant homology to protein kinases.
- the ⁇ 3 ⁇ structure is similar to Class l A p1 10s, but lacks the N-terminal p85 binding site (Domin & Waterfield, 1997). Though similar in overall structure, the homology between catalytic p110 subunits is low to moderate. The highest homology between the PI3K isoforms is in the kinase pocket of the kinase domain.
- the Class l A PI3K isoforms associate with activated receptor tyrosine kinases (RTKs) (including PDGFR, EGFR, VEGFR, IGF1-R, c-KIT, CSF-R and Met), or with tyrosine phosphorylated adapter proteins (such as Grb2, Cbl, IRS-1 or Gabl ) , via their p85 regulatory subunits resulting in stimulation of the lipid kinase activity.
- RTKs receptor tyrosine kinases
- tyrosine phosphorylated adapter proteins such as Grb2, Cbl, IRS-1 or Gabl
- the oncogenic activity of these isoforms may require binding to ras (Kang et ai, 2006).
- the p1 10a and pi 105 isoforms exhibit oncogenic activity independent of ras binding, through constitutive activation of Akt.
- Class I PI3Ks catalyze the conversion of PI (4,5)P 2 [PIP 2 ] to PI (3,4,5)P 3 [PIP 3 ].
- the production of PI P 3 by PI3K affects multiple signaling processes that regulate and coordinate the biological end points of cell proliferation, cell survival, differentiation and cell migration.
- PIP 3 is bound by Pleckstrin-Homology (PH) domain-containing proteins, including the phosphoinositide-dependent kinase, PDK1 and the Akt proto-oncogene product, localizing these proteins in regions of active signal transduction and also contributing directly to their activation (Klippel et ai, 1997; Fleming et ai, 2000; Itoh & Takenawa, 2002; Lemmon, 2003). This co-localization of PDK1 with Akt facilitates the phosphorylation and activation of Akt.
- PH Pleckstrin-Homology
- Akt Carboxy-terminal phosphorylation of Akt on Ser 473 promotes phosphorylation of Thr 308 in the Akt activation loop (Chan & Tsichlis, 2001 ; Hodgkinson et al., 2002; Scheid et al., 2002; Hresko et al., 2003).
- Akt phosphorylates and regulates multiple regulatory kinases of pathways that directly influence cell cycle progression and cell survival. Many of the effects of Akt activation are mediated via its negative regulation of pathways which impact cell survival and which are commonly dysregulated in cancer.
- Akt promotes tumor cell survival by regulating components of the apoptotic and cell cycle machinery.
- Akt is one of several kinases that phosphorylate and inactivate pro-apoptotic BAD proteins (del Peso et al., 1997; Pastorino et al., 1999). Akt may also promote cell s u rviva l th roug h bl ocki n g cytoch rom e C-dependent caspase activation by phosphorylating Caspase 9 on Ser 196 (Cardone et al., 1998).
- Akt impacts gene transcription on several levels.
- the Akt-mediated phosphorylation of the MDM2 E3 ubiquitin ligase on Ser 166 and Ser 186 facilitates the nuclear import of MDM2 and the formation and activation of the ubiquitin ligase complex.
- Nuclear MDM2 targets the p53 tumor suppressor for degradation, a process that can be blocked by LY294002 (Yap et al., 2000; Ogawara et al., 2002). Downregulation of p53 by MDM2 negatively impacts the transcription of p53-regulated pro-apoptotic genes (e.g.
- Forkhead activity also impacts pro-apoptotic and pro-angiogenic gene transcription including the transcription of Fas ligand (Ciechomska et al., 2003) Bim, a pro-apoptotic Bcl-2 family member (Dijkers et al., 2000), and the Angiopoietin-1 (Ang-1) antagonist, Ang-2 (Daly et al., 2004).
- Fas ligand Ciechomska et al., 2003
- Bim a pro-apoptotic Bcl-2 family member
- Ang-1 Angiopoietin-1
- Ang-2 Angiopoietin-1
- Forkhead transcription factors regulate the expression of the cyclin-dependent kinase (Cdk) inhibitor p27 Kip1 .
- PI3K inhibitors have been demonstrated to induce p27 Kip1 expression resulting in Cdk1 inhibition, cell cycle arrest and apoptosis (Dijkers et al., 2000).
- Akt is also reported to phosphorylate p21 Cip1 on Thr 145 and p27 Ki 1 on Thr 157 facilitating their association with 14-3-3 proteins, resulting in nuclear export and cytoplasmic retention, preventing their inhibition of nuclear Cdks (Zhou et al., 2001 ; Motti et al., 2004; Sekimoto et al., 2004).
- Akt phosphorylates IKK (Romashkova & Makarov, 1999), leading to the phosphorylation and degradation of ⁇ and subsequent nuclear translocation of N FKB, resulting in the expression of survival genes such as IAP and Bcl-X L .
- Akt is postulated to suppress JN K and p38 MAPK signaling through the phosphorylation and inhibition of two J N K/p38 regulatory kinases, Apoptosis Signal-regulating Kinase 1 (ASK1) (Kim et al., 2001 ; Liao & Hung, 2003; Yuan et al., 2003), and Mixed Lineage Kinase 3 (M LK3) (Lopez-llasaca et al., 1997; Barthwal et al., 2003; Figueroa et al., 2003).
- ASK1 Apoptosis Signal-regulating Kinase 1
- M LK3 Mixed Lineage Kinase 3
- inhibitors of the PI3K pathway may promote the activities of coadministered cytotoxic drugs.
- GSK3 activity is elevated in quiescent cells, where it phosphorylates cyclin Di on Ser 286 , targeting the protein for ubiquitination and degradation (Diehl et ai, 1998) and blocking entry into S- phase.
- Akt inhibits GSK3 activity through phosphorylation on Ser 9 (Cross et ai, 1995). This results in the elevation of Cyclin Di levels which promotes cell cycle progression.
- Inhibition of GSK3 activity also impacts cell proliferation through activation of the wnt/beta-catenin signaling pathway (Abbosh & Nephew, 2005; Naito et ai, 2005; Wilker et al., 2005; Segrelles et ai, 2006).
- Akt mediated phosphorylation of GSK3 results in stabilization and nuclear localization of the beta-catenin protein, which in turn leads to increased expression of c-myc and cyclin D1 , targets of the beta-catenin/Tcf pathway.
- PI3K signaling is utilized by many of the signal transduction networks associated with both oncogenes and tumor suppressors, PI3K and its activity have been linked directly to cancer.
- Overexpression of both the p1 10a and ⁇ 1 10 ⁇ isoforms has been observed in bladder and colon tumors and cell lines, and overexpression generally correlates with increased PI3K activity (Benistant et ai, 2000).
- Overexpression of ⁇ 110 ⁇ has also been reported in ovarian and cervical tumors and tumor cell lines, as well as in squamous cell lung carcinomas.
- PI3K activity has been observed in colorectal carcinomas (Phillips et al., 1998) and increased expression has been observed in breast carcinomas (Gershtein et al., 1999).
- PIK3CA is mutated in approximately 32% of colorectal cancers (Samuels et al., 2004; Ikenoue et ai, 2005), 1 8-40% of breast cancers (Bachman et al., 2004; Campbell et al., 2004; Levine et al., 2005; Saal et ai, 2005; Wu et ai, 2005), 27% of glioblastomas (Samuels et al., 2004; Hartmann et ai, 2005; Gallia et al., 2006), 25% of gastric cancers (Samuels et al., 2004; Byun et al., 2003; Li et al., 2005), 36% of hepatocellular carcinomas (Lee et al., 2005), 4-12% of
- PIK3CA mutations have been reported in oligodendroma, astrocytoma, medulloblastoma, and thyroid tumors as well (Broderick et al., 2004; Garcia-Rostan et al., 2005). Based upon the observed high frequency of mutation, PIK3CA is one of the two most frequently mutated genes associated with cancer, the other being K-ras. More than 80% of the PIK3CA mutations cluster within two regions of the protein, the helical (E545K) and catalytic (H1047R) domains.
- siRNA-mediated downregulation of ⁇ ⁇ inhibits both Akt phosphorylation and HeLa cell tumor growth in nude mice (Czauderna et al., 2003).
- siRNA-mediated downregulation of ⁇ ⁇ was also shown to inhibit the growth of malignant glioma cells in vitro and in vivo (Pu et al., 2006). Inhibition of PI3K function by dominant-negative p85 regulatory subunits can block mitogenesis and cell transformation (Huang et al., 1996; Rahimi et al., 1996).
- Overexpression of Class I PI3K activity, or stimulation of their lipid kinase activities, is associated with resistance to both targeted (such as imatinib and tratsuzumab) and cytotoxic chemotherapeutic approaches, as well as radiation therapy (West et ai, 2002; Gupta et al., 2003; Osaki et ai, 2004; Nagata et ai, 2004; Gottschalk et ai, 2005; Kim et ai, 2005).
- Activation of PI3K has also been shown to lead to expression of multidrug resistant protein-1 (MRP-1 ) in prostate cancer cells and the subsequent induction of resistance to chemotherapy (Lee et ai, 2004).
- MRP-1 multidrug resistant protein-1
- PI3K signaling in tumorigenesis is further underscored by the findings that the PTEN tumor suppressor, a PI(3)P phosphatase, is among the most commonly inactivated genes in human cancers (Li et ai, 1997; Steck et ai, 1997; AN et ai, 1999; Ishii et ai, 1999). PTEN dephosphorylates PI(3,4,5)P 3 to PI(4,5)P 2 thereby antagonizing PI3K-dependent signaling.
- Cells containing functionally inactive PTEN have elevated levels of PIP 3 , high levels of activity of PI3K signaling (Haas-Kogan et ai, 1998; Myers et ai, 1998; Taylor et ai, 2000), increased proliferative potential, and decreased sensitivity to pro-apoptotic stimuli (Stambolic et ai, 1998).
- Reconstitution of a functional PTEN suppresses PI3K signaling (Taylor et al., 2000), inhibits cell growth and re- sensitizes cells to pro-apoptotic stimuli (Myers et al., 1998; Zhao et ai, 2004).
- M EFs murine embryonic fibroblasts
- RTK Receptor Tyrosine Kinase
- p1 10 ⁇ catalytic activity is required for AKT activation in response to GPCR ligands (such as LPA).
- GPCR ligands such as LPA
- p1 10a appears to carry the majority of the PI3K signal in classic RTK signaling and is responsible for tumor cell growth, proliferation, survival, angiogenesis and metabolism, whereas ⁇ 1 10 ⁇ mediates GPCR signaling from mitogens and chemokines and therefore may regulate tumor cell proliferation, metabolism, inflammation and invasion (Vogt et ai, 2009; Jia et ai, 2009).
- PTEN-deficient human cancer cell lines e.g., PC-3, U87MG, and BT549
- ⁇ 1 10 ⁇ inhibits downstream activation of AKT, cell transformation, and the growth of PTEN-deficient cells and tumor xenografts
- Genetic studies have suggested that the kinase activity of p1 10 ⁇ is essential in cellular transformation caused by PTEN loss. For example, adding back a kinase-dead ⁇ 1 10 ⁇ , but not its wild-type counterpart, impaired focus formation in PTEN-deficient PC3 cells depleted for endogenous p1 10 ⁇ (Wee et al. , 2008).
- PI K3CA and loss-of-function of PTEN were found i n 30-50% and 35-60% of gastric cancer patients, respectively, although PI K3CA and PTEN mutation rate was reported to be less than 7% of each (Byun et al., 2003; Oki et ai, 2006; Li et ai, 2005; Sanger Database).
- tumor types While a subset of tumor types are solely dependent on PI3Ka signaling, other tumors are dependent on ⁇ 3 ⁇ signaling or on a combination of both PI3Ka and ⁇ 3 ⁇ signaling.
- WO 2008/070150 (Bayer Schering Pharma GmbH) relates to 2,3- dihydroimidazo[1 ,2-c]quinazoline compounds, to pharmaceutical compositions containing such compounds and the use of such compounds or compositions for phosphotidylinositol-3-kinase (PI3K) inhibition, and treating diseases associated with P I 3 K activity, in pa rticu lar treati ng hyper-proliferative and/or angiogenesis disorders, as a sole agent or in combination with other active ingredients. Said compounds show an increased activity (lower IC50) against PI3K alpha than against PI3k beta.
- the compounds of the present invention display surprising balanced activity for the inhibition of phosphatidylinositol-3-kinase alpha- and beta- isoforms as shown in the biologiocal section of this text, which is shown as the ratio PI3K beta IC50 / PI3K alpha IC50 .
- the compounds of the present invention exhibit antiproliferative activity and are thus useful to prevent or treat the disorders associated with hyper-proliferation : in particular, said compounds of general formula (I) of the present invention may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth , proliferation and /or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by the PI3K pathway, such as, for example, haemotological tumours, solid tumours, and/or metastases thereof, e.g.
- the PI3K pathway such as, for example, haemotological tumours, solid tumours, and/or metastases thereof, e.g.
- leukaemias and myelodysplastic syndrome including leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
- One embodiment of this invention encompasses a compound having the general formula (I):
- R 1 represents (CH 2 )n-(CHR 4 )-(CH 2 ) m -N(R
- R 2 represents a heteroaryl of structure :
- X represents N or C-R 6
- X' represents 0, S, NH, N-R 6 , N or C-R 6 ,
- R 3 is methyl
- R 4 is hydroxy
- R 5 and R 5' are the same or different and are, independently of each other, a hydrogen atom, or a d -C6-alkyl, C 3 -C6-cycloalkyl-CrC6-alkyl, or Ci-C 6 -alkoxy- Ci-C 6 -alkyl,
- R 5 and R 5' taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R 6' groups ; each occurrence of R 6 may be the same or different and is independently a hydrogen atom, a halogen atom, Ci -C 6 -alkyl, C2-C 6 -alkenyl, C2-C 6 -alkynyl, C 3 - C 6 -cycloalkyl, C 3 -C6-cycloalkyl-CrC6-alkyl, aryl, aryl-Ci-C 6 -alkyl, heteroaryl, heteroaryl-Ci-C 6 -alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-CrC6-alkyl, -Ci-C 6 -alky
- halogen atom or halo is to be understood as meaning a fluorine, chlorine, bromine or iodine atom.
- C C 6 -alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl, 2-methylbutyl, 1 -methylbutyl, 1 - ethylpropyl, 1 , 2-dimethylpropyl, neo-pentyl, 1 , 1 -dimethylpropyl, 4- methylpentyl, 3-methylpentyl, 2-methylpentyl, 1 -methylpentyl, 2-ethylbutyl, 1 -ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1 , 1 , 1
- said group has 1 , 2 or 3 carbon atoms ("CrC 3 -alkyl”), methyl, ethyl, n-propyl- or iso-propyl.
- the term "d-C 6 -alkoxy” is to be understood as preferably meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula -O-alkyl, in which the term "alkyl” is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, sec-butoxy, pentoxy, iso- pentoxy, or n-hexoxy group, or an isomer thereof.
- Ci-C 6 -alkoxy-CrC 6 -alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a Ci-C 6 -alkoxy group, as defined supra, e.g.
- C 2 -C6-alkenyl is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group, which contains one or more double bonds, and which has 2, 3, 4, 5, or 6 carbon atoms, particularly 2 or 3 carbon atoms (“C2-C3-alkenyl”), it being understood that in the case in which said alkenyl group contains more than one double bond, then said double bonds may be isolated from, or conjugated with, each other.
- Said alkenyl group is, for example, a vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (E)- but-2-enyl, (Z)-but-2-enyl, (E)-but-l -enyl, (Z)-but-l -enyl, pent-4-enyl, (E)- pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1 -enyl, (Z)-pent-1 -enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)- hex-3-enyl, (E )-hex-2-enyl, (Z)-hex-2-en
- C 2 -C6-alkynyl is to be understood as preferably meaning a linear or branched, monovalent hydrocarbon group which contains one or more triple bonds, and which contains 2, 3, 4, 5, or 6 carbon atoms, particularly 2 or 3 carbon atoms ("C2-C3-alkynyl").
- Said C2-C 6 -alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1- ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-inyl, hex-3-inyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut- 3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3- methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-4
- C 3 -C6-cycloalkyl is to be understood as preferably meaning a saturated, monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5, or 6 carbon atoms.
- Said C 3 -C 6 -cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group, or a bicyclic hydrocarbon ring, e.g. a perhydropentalenylene or decalin ring.
- Said cycloalkyl ring can optionally contain one or more double bonds e.g.
- cycloalkenyl such as a cyclopropenyl, cyclobutenyl, cyclopentenyl or cyclohexenyl group, wherein the bond between said ring with the rest of the molecule may be to any carbon atom of said ring, be it satu rated or unsaturated.
- alkylene is understood as preferably meaning an optionally substituted hydrocarbon chain (or “tether”) having 1 , 2, 3, 4, 5, or 6 carbon atoms, i.e. an optionally substituted -CH 2 - ("methylene” or “single membered tether” or, for example -C(Me) 2 -), -CH2-CH2- ("ethylene”, “dimethylene”, or “two-membered tether"), -CH2-CH2-CH2- ("propylene”, “trimethylene”, or “three-membered tether"), -CH2-CH2-CH2-CH2- ("butylene”, “tetramethylene”, or “four-membered tether"), -CH2-CH2-CH2-CH2- ("pentylene”, “pentamethylene” or “five-membered ether”), or -CH2-CH2-CH2-CH2-CH2- (“hexylene”, “hexamethylene”, or six-membered tether”) group.
- methylene or "sing
- said 3- to 8-membered heterocycloalkyl can contain 2, 3, 4, 5, 6 or 7 carbon atoms, and one or more of the above-mentioned heteroatom- containing groups (a "3- to 8-membered heterocycloalkyl"), more particularly said heterocycloalkyl can contain 4 or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "5- to 7-membered heterocycloalkyl").
- said heterocycloalkyl can be a 4- membered ring, such as an azetidinyl, oxetanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl, or a 7- membered ring, such as a diazepanyl ring, for example.
- said heterocycloalkyl can be benzo fused.
- Said heterocyclyl can be bicyclic, such as, without being limited thereto, a 5, 5-membered ring, e. g. a hexahydrocyclopenta[c]pyrrol-2(1 H)-yl) ring, or a 5,6-membered bicyclic ring, e. g . a hexahydropyrrolo[1 ,2-a]pyrazin-2(1 H)-yl ring, or 8-oxa-3-azabicyclo[3.2.1]oct-3-yl ring, for example.
- a 5, 5-membered ring e. g. a hexahydrocyclopenta[c]pyrrol-2(1 H)-yl) ring
- a 5,6-membered bicyclic ring e. g . a hexahydropyrrolo[1 ,2-a]pyrazin-2(1 H)-yl ring
- said nitrogen atom-containing ring can be partially unsaturated, i. e. it can contain one or more double bonds, such as, without being limited thereto, a 2, 5-dihydro- 1 H-pyrrolyl, 4H-[1 , 3,4]thiadiazinyl, 4, 5- dihydrooxazolyl, or 4H-[1 ,4]thiazinyl ring, for example, or, it may be benzo- fused, such as, without being limited thereto, a dihydroisoquinolinyl ring, for example.
- aryl is to be understood as preferably meaning a monovalent, aromatic or partially aromatic, mono-, or bi- or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 carbon atoms (a "C6-Ci 4 -aryl” group), particularly a ring having 6 carbon atoms (a "C6-aryl” group), e.g. a phenyl group; or a biphenyl group, or a ring having 9 carbon atoms (a "Cg-aryl” group), e.g. an indanyl or indenyl group, or a ring having 10 carbon atoms (a "Cio-aryl” group), e.g.
- a particular example of an aryl group is one of the following possible structures : in which z represents 0, S, NH or N(d-C6-alkyl), and * indicates the point of attachment of said aryl group with the rest of the molecule.
- heteroaryl is understood as preferably meaning a monovalent, monocyclic- , bicyclic- or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl” group), particularly 5 or 6 or 9 or 10 atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulfur, and in addition in each case can be benzocondensed.
- heteroaryl is of structure :
- X represents N or C-R 6 .
- X' represents O, S, NH, N-R 6 , N or C-R 6 ,
- R 7 and R 7' may be the same or different and is independently a hydrogen atom, or a Ci-C6-alkyl, C 2 -C 6 -alkenyl, C 2 -C6- alkynyl, C3-C 6 -cycloalkyl, C3-C6-cycloalkyl-CrC6-alklyl, C3-C6- cycloalkenyl, aryl, aryl-Ci-C 6 -alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-CrC6-alkyl, or heteroaryl-CrC6-alkyl ;
- R 8 is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, Ci-C 6 -alkyl, Ci-C 6 -alkoxy, C 2 -
- said heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl etc.
- benzo derivatives thereof such as, for exam ple, benzof u ranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc.; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. , and benzo derivatives thereof, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl, etc.; or azocinyl, indolizinyl, purinyl, etc.
- the heteroarylic or heteroarylenic radicals include all the possible isomeric forms thereof, e.g. the positional isomers thereof.
- the term pyridinyl or pyridinylene includes pyridin-2-yl, pyridin-2-ylene, pyridin-3-yl, pyridin-3-ylene, pyridin-4-yl and pyridin-4-ylene; or the term thienyl or thienylene includes thien-2-yl, thien-2-ylene, thien-3-yl and thien-3-ylene.
- C1 -C6 as used throughout this text, e.g. in the context of the definition of "CrC6-alkyl” or “C C6-alkoxy” is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1 , 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C1 -C6” is to be interpreted as any sub-range comprised therein, e.g.
- C2-C6 as used throughout this text, e.g. in the context of the definitions of "C2-C6-alkenyl” and “C2-C6-alkynyl”, is to be understood as meaning an alkenyl group or an alkynyl group having a finite number of carbon atoms of 2 to 6, i. e. 2, 3, 4, 5, or 6 carbon atoms. It is to be understood further that said term “C2-C6” is to be interpreted as any sub- range comprised therein, e.g. C2-C6 , C3-C5 , C3-C 4 , C2-C3 , C2-C 4 , C2-C5 ; particularly
- C3-C6 as used throughout this text, e.g. in the context of the definition of "C3-C6-cycloalkyl”, is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term “C3- C 6 " is to be interpreted as any sub-range comprised therein, e.g. C3-C6 , C 4 -Cs , C3-C5 , C 3 -C 4 , C 4 -C 6 , C 5 -C 6 ; particularly C 3 -C 6 .
- substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded , and that the substitution resu lts i n a stab le com pound . Combinations of substituents and /or variables are permissible only if such combinations result in stable compounds.
- optionally substituted means optiona l substitution with the specified groups, radicals or moieties.
- Ring system substituent means a substituent attached to an aromatic or nonaromatic ring system which, for example, replaces an available hydrogen on the ring system.
- the term "one or more times”, e.g. in the definition of the substituents of the com pounds of the general form ulae of the present invention, is understood as meaning “one, two, th ree, four or five times, particularly one, two, three or four times, more particularly one, two or three times, even more particularly one or two times".
- stable compound or " stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
- carbonyl refers to an oxygen atom bound to a carbon atom of the molecule by a double bond.
- the compounds of this invention may contain one or more asymmetric centers, depending upon the location and nature of the various substituents desired.
- Asymmetric carbon atoms may be present in the (R)- or (Sj-configuration, resulting in racemic mixtures in the case of a single asymmetric center, and diastereomeric mixtures in the case of multiple asymmetric centers.
- asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
- Substituents on a ring may also be present in either cis or trans form . It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention.
- Preferred compounds are those, which produce the more desirable biological activity.
- Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention.
- the purification and the separation of such materials can be accomplished by standard techniques known in the art.
- Tautomers are two or more compounds that are related by the migration of a hydrogen atom accompanied by the switch of one or more single bonds and one or more adjacent double bonds.
- the compounds of this invention may exist in one or more tautomeric forms.
- a compound of Formula I may exist in tautomeric form la, tautomeric form lb, or tautomeric form Ic, or may exist as a mixture of any of these forms. It is intended that all
- the present invention also relates to useful forms of the compounds as disclosed herein , such as pharmaceutically acceptable salts, co-precipitates, metabolites, hydrates, solvates and prodrugs of all the compounds of examples.
- pharmaceutically acceptable salt refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.
- Pharmaceutically acceptable salts include those obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methane sulfonic acid, camphor sulfonic acid, oxalic acid, maleic acid, succinic acid and citric acid.
- Pharmaceutically acceptable salts also include those in which the main compound functions as an acid and is reacted with an appropriate base to form, e.g., sodium, potassium, calcium, magnesium, ammonium, and chorine salts.
- acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
- alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.
- salts of the compounds of this invention include the conventional nontoxic salts and the quaternary ammonium salts which are formed, for example, from inorganic or organic acids or bases by means well known in the art.
- acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, itaconate, lactate, maleate, mandelate, methanesulfonate, 2-naphthal
- Base salts include alkali metal salts such as potassium and sodium salts, alkaline earth metal salts such as calcium and magnesium salts, and ammonium salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. Additionally, basic nitrogen containing groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, or butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl sulfate, or diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.
- lower alkyl halides such as methyl, ethyl, propyl, or butyl chlorides,
- a solvate for the purpose of this invention is a complex of a solvent and a compound of the invention in the solid state.
- Exemplary solvates would include, but are not limited to, complexes of a compound of the invention with ethanol or methanol. Hydrates are a specific form of solvate wherein the solvent is water.
- the invention encompasses the compound of Formula (I), wherein : R 1 represents (CH2)n-(CHR 4 )-(CH 2 ) m -N(R);
- R 2 represents a heteroaryl of structure :
- R 3 is methyl
- R 4 is hydroxy
- R 5 and R 5 ' are the same or different and are, independently of each other, a hydrogen atom, or a d-C 6 -alkyl, C3-C 6 -cycloalkyl-CrC 6 -alkyl, or Ci -C 6 -alkoxy- Ci -C 6 -alkyl,
- R 5 and R 5 ' taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R 6 ' groups ; each occurrence of R 6 may be the same or different and is independently a hydrogen atom, a halogen atom, Ci -C 6 -alkyl, C2-C 6 -alkenyl, C2-C 6 -alkynyl, C 3 - C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-CrC 6 -alkyl, aryl, aryl-Ci -C 6 -alkyl, heteroaryl, heteroaryl-CrC 6 -alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-CrC 6 -alkyl, -Ci -
- * represents the point of attachment with the rest structure of general formula (I). or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same.
- the invention encompasses the compound of Formula (I), wherein
- R 1 represents (CH2)n-(CHR 4 )-(CH 2 ) m -N(R)
- R 2 represents a heteroaryl of structure :
- R 3 is methyl
- R 4 is hydroxy
- R 5 and R 5 ' are the same or different and are, independently of each other, a hydrogen atom, or a d-C6-alkyl, C3-C6-cycloalkyl-CrC6-alkyl, or Ci -C 6 -alkoxy- Ci -C 6 -alkyl,
- R 5 and R 5 ' taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R 6 ' groups ; each occurrence of R 6 may be the same or different and is independently a hydrogen atom, a halogen atom, Ci -C6-alkyl, C2-C 6 -alkenyl, C2-C 6 -alkynyl, C 3 - C 6 -cycloalkyl, C 3 -C6-cycloalkyl-CrC6-alkyl, aryl, aryl-Ci -C 6 -alkyl, heteroaryl, heteroaryl-CrC6-alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-CrC6-alkyl, -Ci -C 6 -al
- * represents the point of attachment with the rest of the structure of general formula (I). or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, in particular a physiologically acceptable salt, or a mixture of same.
- the invention encompasses the compound of Formula (I), wherein :
- R 1 represents (CH2)n-(CHR 4 )-(CH 2 ) m -N(R 5 )(R 5 ' ) ;
- R 2 represents a heteroaryl of structure :
- Z represents N or C-R 6 ;
- R 3 is methyl
- R 4 is hydroxy
- R 5 and R 5 ' are the same or different and are, independently of each other, a hydrogen atom, or a d-C6-alkyl, C3-C6-cycloalkyl-CrC6-alkyl, or Ci -C 6 -alkoxy- Ci -C 6 -alkyl,
- R 5 and R 5 ' taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R 6 ' groups ; each occurrence of R 6 may be the same or different and is independently a hydrogen atom, a halogen atom, Ci -C 6 -alkyl, C2-C 6 -alkenyl, C2-C 6 -alkynyl, C 3 - C 6 -cycloalkyl, C 3 -C6-cycloalkyl-CrC6-alkyl, aryl, aryl-Ci -C 6 -alkyl, heteroaryl, heteroaryl-CrC6-alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-CrC6-alkyl, -Ci -C 6 -
- the invention encompasses the compound of Formula (I), wherein : R 1 represents (CH2)n-(CHR 4 )-(CH 2 ) m -N(R 5 )(R 5 ' ) ;
- R 2 represents a heteroaryl of structure :
- Z represents N or C-R 6 ;
- R 3 is methyl
- R 4 is hydroxy
- R 5 and R 5' are the same or different and are, independently of each other, a hydrogen atom, or a Ci -C 6 -alkyl, C3-C6-cycloalkyl-CrC6-alkyl, or Ci -C 6 -alkoxy- Ci -C 6 -alkyl,
- R 5 and R 5' taken together with the nitrogen atom to which they are bound, represent a 3- to 7-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R 6' groups ; each occurrence of R 6 may be the same or different and is independently a hydrogen atom, a halogen atom, Ci -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 - C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-CrC 6 -alkyl, aryl, aryl-Ci-C 6 -alkyl, heteroaryl, heteroaryl-CrC 6 -alkyl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-CrC 6 -alkyl, -Ci
- R 1 represents (CH2)n-(CHR 4 )-(CH 2 ) m -N(R 5 )(R 5 ' ) ;
- the invention relates to compounds of formula (I), wherein
- R 2 represents a heteroaryl of structure :
- X represents N or C-R 6 .
- X' represents 0, S, NH, N-R 6 , N or C-R 6 ,
- the invention relates to compounds of formula (I), wherein
- R 3 is methyl
- the invention relates to compounds of formula (I), wherein
- R 4 is hydroxy
- the invention relates to compounds of formula (I), wherein
- R 5 and R 5' are the same or different and are, independently of each other, a hydrogen atom, or a d-C6-alkyl, CrC6-cycloalkyl-CrC6-alkyl, or Ci -C 6 -alkoxy- Ci -C 6 -alkyl, or
- R 5 and R 5 ' taken together with the nitrogen atom to which they are bound, represent a 3- to 8-membered nitrogen containing heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, nitrogen or sulfur and which may be optionally substituted with 1 or more R 6 ' groups ;
- the invention relates to compounds of formula (I), wherein
- the invention relates to compounds of formula (I), wherein
- each occurrence of R 6 ' may be the same or different and is independently Cr
- the invention relates to compounds of formula (I), wherein
- each occurrence of R 7 and R 7 ' may be the same or different and is independently a hydrogen atom, or a Ci -C 6 -alkyl, C2-C 6 -alkenyl, C2-C 6 -alkynyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-CrC 6 -alklyl, C 3 -C 6 -cycloalkenyl, aryl, aryl-Cr C 6 -alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, 3- to 8-membered heterocyclyl-CrC 6 -alkyl, or heteroaryl-C C 6 -alkyl ;
- the invention relates to compounds of formula (I), wherein each occurrence of R 8 is independently a halogen atom, or nitro, hydroxy, cyano, formyl, acetyl, amino, d-C6-alkyl, Ci -C 6 -alkoxy, C2-C 6 -alkenyl, C2-C6- alkynyl, C3-C 6 -cycloalkyl, C3-C6-cycloalkyl-CrC6-alkyl, Ci -C6-cycloalkenyl, aryl, aryl-Ci -C 6 -alkyl, heteroaryl, 3- to 8-membered heterocyclic ring, heterocyclyl- Ci -C 6 -alkyl, or heteroaryl-Ci -C 6 -alkyl ;
- the invention relates to compounds of formula (I), wherein
- n is an integer of 1 and m is an integer of 1 ; with the proviso that when :
- R 2 represents a heteroaryl of structure :
- the invention relates to compounds of formula (I), wherein
- R 2 represents a heteroaryl of structure :
- Z represents N or C-R 6 ;
- the invention relates to compounds of formula (I), according to any of the above-mentioned embodiments, in the form of or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of same.
- the present i nvention relates to any subcombination within any embodiment of the present invention of compounds of general formula (I), supra. More particularly still, the present invention covers compounds of general formula (I) which are disclosed in the Example section of this text, infra. In accordance with another aspect, the present invention covers a method of preparing compounds of the present invention, the method comprising the steps as described herein.
- the present invention covers intermediate compounds which are useful in the preparation of compounds of the present invention of general formula (I), particularly in the method described herein.
- the present invention covers compounds of general formula (XI) :
- the present invention covers the use of the intermediate compounds of general formula (XI ), supra, fo r th e preparation of the compounds of the present invention of general formula (I), supra.
- the compounds of the invention can be made according to conventional chemical methods, and/or as disclosed below, from starting materials which are either commercially available or producible according to routine, conventional chemical methods. General methods for the preparation of the compounds are given below, and the preparation of representative compounds is specifically illustrated in examples.
- Synthetic transformations that may be employed in the synthesis of compounds of this invention and in the synthesis of intermediates involved in the synthesis of compounds of this invention are known by or accessible to one skilled in the art. Collections of synthetic transformations may be found in compilations, such as:
- PG refers to a suitable protecting group, well-known to the person skilled in the art, e.g. from T.W. Greene; P.G.M. Wuts. Protective Groups in Organic Synthesis, 3rd ed.; John Wiley: New York (1999).
- aprotic solvent such as THF or dioxane.
- Reduction of the nitro group in formula (VI) could be accomplished using iron in acetic acid or hydrogen gas in the presence of a suitable palladium, platinum or nickel catalyst.
- Conversion of compounds of formula (VII) to the imidazoline of formula (VIII) is best accomplished using ethylenediamine in the presence of a catalyst such as elemental sulfur with heating.
- the cyclization of compounds of formula (VIII) to those of formula (IX) is accomplished using cyanogen bromide in the presence of an amine base such as triethylamine, diisopropylethylamine, or pyridine in a halogenated solvent such as DCM or dichloroethane. Removal of the protecting group in formula (IX) will be dependent on the group selected and can be accomplished by standard methods (Greene, T.W.;
- Alkylation of the phenol in formula (X) can be achieved using a base such as caesium carbonate, sodium hydride, or potassium t-butoxide in a polar aprotic solvent such as DMF or DMSO with introduction of a side chain bearing an appropriate leaving group such as a halide, or a sulfonate group, to provide compounds of formula (XI).
- a base such as caesium carbonate, sodium hydride, or potassium t-butoxide in a polar aprotic solvent such as DMF or DMSO
- a side chain bearing an appropriate leaving group such as a halide, or a sulfonate group
- amides of formula (I) can be formed using activated esters such as acid chlorides and anhydrides or alternatively formed using carboxylic acids and appropriate coupling agents such as PYBOP, DCC, or EDCI in polar aprotic solvents.
- a compound of formula (IV), prepared as described above, can be converted to a structure of formula (XII) using ammonia in the presence of iodine in an aprotic solvent such as THF or dioxane.
- Alkylation of the phenol in formula (XII) can be achieved using a base such as caesium carbonate, sodium hydride, or potassium t- butoxide in a polar aprotic solvent such as DMF or DMSO with introduction of a side chain bearing an appropriate leaving group such as a halide, or a sulfonate group.
- Reduction of the nitro group in formula (XIII) could be accomplished using iron in acetic acid or hydrogen gas in the presence of a suitable palladium, platinum or nickel catalyst.
- Conversion of compounds of formula (XIV) to the imidazoline of formula (XV) is best accomplished using ethylenediamine in the presence of a catalyst such as elemental sulfur with heating.
- the cyclization of compounds of formula (XV) to those of formula (XVI) is accomplished using cyanogen bromide in the presence of an amine base such as triethylamine, diisopropylethylamine, or pyridine in a halogenated solvent such as DCM or dichloroethane.
- amides of formula (I) can be formed using activated esters such as acid chlorides and anhydrides or alternatively formed using carboxylic acids and appropriate coupling agents such as PYBOP, DCC, or EDCI in polar aprotic solvents.
- a compound of formula (X), prepared as described above, can be converted to amide (XVI) using activated esters such as acid chlorides and anhydrides or alternatively formed using carboxylic acids and appropriate coupling agents such as PYBOP, DCC, or EDCI in polar aprotic solvents.
- This could then be converted to compounds of formula (I) using a base such as caesium carbonate, sodium hydride, or potassium t-butoxide in a polar aprotic solvent such as DMF or DMSO with introduction of a side chain bearing an appropriate leaving group such as a halide, or a sulfonate group.
- a base such as caesium carbonate, sodium hydride, or potassium t-butoxide
- a polar aprotic solvent such as DMF or DMSO
- a compound of formula (IX), prepared as described above, can be converted to amide (XVII) using activated esters such as acid chlorides and anhydrides or alternatively formed using carboxylic acids and appropriate coupling agents such as PYBOP, DCC, or EDCI in polar aprotic solvents. Removal of the protecting group in formula (XVII) will be dependent on the group selected and can be accomplished by standard methods (Greene, T.W.; Wuts, P.G.M.; Protective Groups in Organic Synthesis; Wiley & Sons: New York, 1999).
- Alkylation of the phenol in formula (XVI) can be achieved using a base such as caesium carbonate, sodium hydride, or potassium t-butoxide in a polar aprotic solvent such as DMF or DMSO with introduction of a side chain bearing an appropriate leaving group such as a halide, or a sulfonate group.
- a compound of formula XVIII can be converted to the bis chloride compound of formula XIX using chlorinating agents such as POCI 3 or COCI 2 in aprotic solvents.
- the chloride thus obtained can be converted to imidazolines of formula XXI through reaction with appropriate quantities of ethanolamine or a suitably protected substitute, followed by activation with a suitable activating agent such as a sulfonyl chloride, PPh 3 , or an halogenating agent such as SOCI 2 .
- Chloride XXI can be converted to amine XXI I through the use of any source of nucleophilic amine such as ammonia, phthalimide, or protected amines such as benzyl amine.
- Celite® diatomaceous earth filter agent Celite ® Corp.
- rel refers to a compound in which one chiral center is not defined, said chiral center being in the presence of one or more other chiral centers which are defined
- TBDPS TPS tert-butyldiphenylsilyl TEA triethylamine
- Method 1 99% 0.1% aqueous Formic Acid : 1% CH 3 CN to 1% 0.1% aqueous Formic Acid : 99% CH 3 CN over 1.6 min.; 1% 0.1% aqueous Formic Acid : 99% CH 3 CN over 1.6 min. for 0.4 min.
- Method 2 99% 0.2% aqueous Ammonia : 1% CH 3 CN to 1% 0.1% aqueous Ammonia : 99% CH 3 CN over 1.6 min.; 1% 0.1% aqueous Ammonia : 99% CH 3 CN over 1.6 min. for 0.4 min.
- analytical HPLC utilized Method 2.
- M PLC medium pressure liquid chromatography
- MPLC purifications were conducted using a Flash Master I I chromatograph equipped with an Isolute Flash NH 2 reverse phase column eluting with a mixed solvent gradient (100% CH 2 CI 2 for 3 min., gradient to 90% CH 2 CI 2 : 10% MeOH over 12 minutes; gradient to 80% CH 2 CI 2 : 20% MeOH over 20 min. ; gradient to 70% CH 2 CI 2 : 30% MeOH over 10 min.; and gradient to 50% CH 2 CI 2 : 50% MeOH over 15 min.) at the flow rate recommended for the column size (i.e., 5 g column, 10 mL/min.; 50 g column, 30 ml/min.). Eluant was monitored with a UV detector at 254 nm. Determination of optical rotation conditions :
- Optical rotations were measured in DMSO, at 589 nm wavelength, 20° C, concentration 1.0000 g/100ml_, integration time 10 s, film thickness 100.00 mm.
- Routine one-dimensional NMR spectroscopy was performed on either 300 or 400 MHz Varian® Mercury-plus spectrometers. The samples were dissolved in deuterated solvents. Chemical shifts were recorded on the ppm scale and were referenced to the appropriate solvent signals, such as 2.49 ppm for DMSO-d 6 , 1 -93 ppm for CD 3 CN, 3.30 ppm for CD 3 OD, 5.32 ppm for CD 2 CI 2 and 7.26 ppm for CDCI3 for 1 H spectra. The percentage yields reported in the following examples are based on the starting component that was used in the lowest molar amount. Air and moisture sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa.
- Thin layer chromatography was performed on pre-coated glass-backed silica gel 60 A F-254 250 ⁇ plates.
- temperatures are reported uncorrected in degrees Celsius (°C). Names of compounds were generated using ACD/Name Batch version 12.01. In some cases generally accepted names of commercially available reagents were used.
- 3-Morpholin-4-ylpropane-1 ,2-diol (2.1 g, 9.07 mmol) was dissolved in DCM (15 mL) and cooled to 0 °C. The cooled solution was treated with thionyl chloride (1 .81 mL, 24.8 mmol) and then heated at the reflux temperature for 1 h.
- Step 1 Preparation of 4-formyl-2-methoxy-3-nitrophenyl acetate
- Racemic glycidol methanesulfonate was synthesized in a manner analogous to Intermediate F, Step 1, substituting racemic gylcidol for (S)-(-)-glycidol
- the solution of racemic glycidyl methanesulfonate in DMF was used in further transformations without further purification.
- Step 2 Preparation of 7-Methoxy-8-(oxiran-2-ylmethoxy)-2,3-dihydroimidazo[1,2- c]quinazolin-5-amine
- Step 2 Preparation of 7-methoxy-8-[(2S)-oxiran-2-ylmethoxy]-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-amine
- Step 1 Preparation of V-[8-(benzyloxy)-7-methoxy-2,3-dihydroimidazo[1,2- c]quinazolin-5-yl]nicotin
- Step 2 Preparation of V-(8-hydroxy-7-methoxy-2,3-dihydroimidazo[1 ,2- c]quinazolin-5-yl)nicotinamide
- A/-[8-(Benzyloxy)-7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl]nicotinamide (20 g, 45.1 mmol) was added portionwise over 1 h to a round bottom flask containing TFA (400 mL) precooled with an ice bath. The reaction mixture was heated to 60 °C and allowed to stir at this temperature for 17 h at which time it was cooled to room temperature. The reaction mixture was then concentrated under reduced pressure. The resulting residue was dissolved in CH 2 CI 2 and hexane and concentrated under reduced pressure.
- Step 3 Preparation of N-[7-methoxy-8-(oxiran-2-ylmethoxy)-2,3- dihydroimidazo[1 ,2-c]quinazolin-5-yl]nicotinamide
- the resulting mixture was stirred at room temperature for 16 h at 60 °C, then was cooled to room temperature and concentrated under reduced pressure.
- the resulting residue was seperated between water (50 mL) and a 4:1 CH 2 CI 2 / isopropanol solution (50 mL).
- the organic phase was washed with a concentrated sodium bicarbonate solution, dried (anh. sodium sulfate), and concentrated under reduced pressure.
- reaction mixture was treated with another equivalent of 4-[(2-oxido-1 ,3,2- dioxathiolan-4-yl)methyl]morpholine hydrochloride (Intermediate C, Step 2) and stirred at 60 °C overnight.
- the reaction mixture was concentrated under reduced pressure and the product was extracted with a solution of 20% isopropanol/ 80% chloroform and washed with a saturated solution of sodium hydrogen carbonate. The organics were dried (magnesium sulfate) and concentrated under reduced pressure, and the resulting residue was triturated with EtOAc and filtered.
- Example 21 6-amino-/ ⁇ /- ⁇ 8-[2-hvdroxy-3-(morpholin-4-yl)propoxy1-7-methoxy-2,3- dihvdroimidazo[1,2-c1quinazolin-5-yl)pyridine-3-carboxamide
- Step 1 Preparation of (2R)-3-(4-mor holinyl)-1,2-propanediol
- (S)-glycidol (1 .00 mL, 15.0 mmol) and morpholine (1 .96 mL, 22.5 mmol, 2.5 equiv.) in abs. ethanol was heated in a microwave for 4 min.
- Step 2 Preparation of 4-[(4R)-(2-oxido-1 ,3,2-dioxathiolan-4-yl)methyl]morpholine hydrochloride
- Step 3 Preparati on of V-(8- ⁇ [(2R)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy ⁇ -7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide
- This mixture was stirred at 60 °C for 12 hr, cooled to room temperature, treated with additional caesium carbonate (0.86 g, 2.6 mmol, 2.0 equiv.) and cyclic sulfite ester (0.275 g, 1.3 mmol, 1.0 equiv.) and stirred at 60 °C for an additional 12 hr.
- the resulting mixture was concentrated under reduced pressure.
- the residue was dissolved in a 4: 1 CH 2 CI 2 / isopropanol solution (100 mL), then was washed with a saturated sodium bicarbonate solution (50 mL) and a saturated sodium chloride solution (50 mL), dried (anh. sodium sulfate), and concentrated under reduced pressure.
- Step 3 Preparati on of V-(8- ⁇ [(2S)-2-hydroxy-3-(morpholin-4-yl)propyl]oxy ⁇ -7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide
- This mixture was stirred at 60 °C for 12 hr, cooled to room temperature, treated with additional caesium carbonate (0.86 g, 2.6 mmol, 2.0 equiv.) and cyclic sulfite ester (0.076 g, 0.37 mmol, 1.0 equiv.) and stirred at 60 °C for an additional 3.5 days.
- the resulting mixture was concentrated under reduced pressure.
- the residue was dissolved in a 4: 1 CH 2 CI 2 / isopropanol solution (50 mL), then was washed with a saturated NaHC0 3 (25 mL) and a saturated NaCI solution (25 mL), dried (anh. Na 2 S0 4 ), and concentrated under reduced pressure.
- Step 1 Preparation of V-[8-( ⁇ (2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2- hydroxypropyl ⁇ oxy)-7-methox -2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl]amine
- Step 2 Preparation of V-[8-( ⁇ (2R)-3-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-2- hydroxypropyl ⁇ oxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyridine- 3-carboxamide
- Step 1 Preparation of V-(8- ⁇ [(2R)-2-hydroxy-3-(8-oxa-3-azabicyclo[3.2.1]oct-3- yl)propyl]oxy ⁇ -7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-ylamine
- Step 2 Preparation of V-(8- ⁇ [(2R)-2-hydroxy-3-(8-oxa-3-azabicyclo[3.2.1]oct-3- yl)propyl]oxy ⁇ -7-methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3- carboxamide
- Example 17 /V-r8-( ⁇ (2R)-3-r(2R,6S)-2,6-dimethylmorpholin-4-yll-2-hvdroxypropyl)oxy)-
- Example 34 /V-r8-( ⁇ (2R)-3-r(2R,6S)-2,6-dimethylmorpholin-4-yll-2-hvdroxypropyl)oxy)- 7-methoxy-2,3-dihydroimidazo[1 ,2-c1quinazolin-5-yl1-1 ,3-thiazole-5-carboxamide
- Example 11 /V-(8- ⁇ [(2R)-3-(dimethylamino)-2-hvdroxypropyl1oxy)-7-methoxy-2,3- dihvdroimidazo[1,2-c1quinazolin-5-yl)pyridine-3-carboxamide
- Example 12 /V-(8- ⁇ [(2R)-3-(dipropan-2-ylamino)-2-hvdroxypropyl1oxy)-7-methoxy-2,3- dihvdroimidazo[1,2-c1quinazolin-5-yl)pyridine-3-carboxamide
- Example 20 /V-(8- ⁇ [(2R)-3-(dipropan-2-ylamino)-2-hvdroxypropyl1oxy)-7-methoxy-2,3- dihvdroimidazo[1 ,2-c1quinazolin-5-yl)-2-methylpyridine-3-carboxamide
- Example 41 /V-(8- ⁇ [(2R)-3-(dipropan-2-ylamino)-2-hvdroxypropyl1oxy)-7-methoxy-2,3- dihydroimidazo[1 ,2-c1quinazolin-5-yl)-1 ,3-thiazole-5-carboxamide
- Step 1 Preparation of V-(8- ⁇ [(2R)-3-(azetidin-1 -yl)-2-hydroxypropyl]oxy ⁇ -7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)amine
- Step 2 Preparation of V-(8- ⁇ [(2R)-3-(azetidin-1 -yl)-2-hydroxypropyl]oxy ⁇ -7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide
- Step 1 Preparati on of V-(8- ⁇ [(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy ⁇ -7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)amine
- Step 2 Preparati on of V-(8- ⁇ [(2R)-2-hydroxy-3-(pyrrolidin-1 -yl)propyl]oxy ⁇ -7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)pyridine-3-carboxamide
- Example 18 /V-(8- ⁇ r(2R)-2-hvdroxy-3-(pyrrolidin-1-yl)propyl1oxy)-7-methoxy-2,3- dihvdroimidazo[1,2-c1quinazolin-5-yl)-2-methylpyridine-3-carboxamide
- Example 38 A/-(8- ⁇ r(2R)-2-Hvdroxy-3-(pyrrolidin-1-yl)propylloxy)-7-methoxy-2,3- dihvdroimidazo[1 ,2-c1quinazolin-5-yl)-4-methyl-1 ,3-thiazole-5-carboxamide
- Example 40 /V-(8- ⁇ r(2R)-2-Hvdroxy-3-(pyrrolidin-1-yl)propyl1oxy)-7-methoxy-2,3- dihydroimidazo[1 ,2-c1quinazolin-5-yl)-1 ,3-oxazole-5-carboxamide
- Step 1 P reparati o n of V-(8- ⁇ [(2R)-2-Hydroxy-3-(piperidin-1 -yl)propyl]oxy ⁇ -7- methoxy-2,3-dihydroimidazo[1 ,2-c]quinazolin-5-yl)amine
- This mixture was stirred at 60 °C for 12 hr and concentrated under reduced pressure to a volume of approximately 50 mL and divided into 3 portions. Each portion was treated with 2.15 mL piperidine (6.45 mL total, 65.2 mmol, 10 equiv.) and was heated in a microwave reactor for 45 min. at 140 °C. The combined resulting mixtures were concentrated under reduced pressure.
- Example 15 /V-(8- ⁇ [(2S)-2-Hvdroxy-3-(morpholin-4-yl)propyl1oxy)-7-methoxy-2,3- dihvdroimidazo[1,2-c1quinazolin-5-yl)-2-methylpyridine-3-carboxamide
- Example 22 6-Amino-/ ⁇ /-(8- ⁇ [(2S)-2-hvdroxy-3-(morpholiri-4-yl)propyl1oxy)-7-methoxy- 2,3-dihvdroimidazo[1 ,2-c1quinazolin-5-yl)pyridine-3-carboxamide
- Example 30 A/-(8- ⁇ r(2R)-2-Hvdroxy-3-(morpholin-4-yl)propylloxy)-7-methoxy-2,3- dihvdroimidazo[1,2-c1quinazolin-5-yl)-3H-imidazo[4,5-blpyridine-6-carboxamide
- Example 32 A/-(8- ⁇ r(2R)-2-Hvdroxy-3-(morpholin-4-yl)propylloxy)-7-methoxy-2,3- dihydroimidazo[1,2-c1quinazolin-5-yl)-1,3-thiazole-5-carboxamide
- Example 33 A/-(8- ⁇ r(2S)-2-Hvdroxy-3-(morpholin-4-yl)propylloxy)-7-methoxy-2,3- dihvdroimidazo[1,2-clquinazolin-5-yl)-1,3-thiazole-5-carboxamide
- the compounds of formula (I) of the present invention can be converted to any salt as described herein, by any method which is known to the person skilled in the art.
- any salt of a compound of formula (I) of the present invention can be converted into the free compound, by any method which is known to the person skilled in the art.
- compositions containing one or more compounds of the present invention can be utilised to achieve the desired pharmacological effect by administration to a patient in need thereof.
- a patient for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease. Therefore, the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention.
- a pharmaceutically acceptable carrier is preferably a carrier that is relatively non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient.
- a pharmaceutically effective amount of compound is preferably that amount which produces a result or exerts an influence on the particular condition being treated.
- the compounds of the present invention can be administered with pharmaceutically-acceptable carriers well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, and the like.
- the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions.
- the solid unit dosage forms can be a capsule that can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.
- the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatin, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, coloring agents, and flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient.
- binders such as acacia, corn starch or gelatin
- disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn star
- Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent.
- Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.
- Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example those sweetening, flavoring and coloring agents described above, may also be present.
- the pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions.
- the oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils.
- Suitable emulsifying agents may be (1 ) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate.
- the emulsions may also contain sweetening and flavoring agents.
- Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol.
- the suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p- hydroxy benzoate ; one or more coloring agents ; one or more flavoring agents ; and one or more sweetening agents such as sucrose or saccharin.
- Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
- sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose.
- Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavoring and coloring agents.
- the compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in preferably a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2, 2-dimethyl-1 , 1 -dioxolane-4- methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a pharmaceutically acceptable sur
- Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid.
- Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate.
- Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates ; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates ; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene- oxypropylene)s or ethylene oxide or propylene oxide copolymers ; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2- alkylimidazoline quarternary ammonium salts, as well as mixtures.
- suitable detergents include cationic detergents
- compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimise or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile-lipophile balance (HLB) preferably of from about 12 to about 17. The quantity of surfactant in such formulation preferably ranges from about 5% to about 15% by weight.
- the surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.
- surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
- compositions may be in the form of sterile injectable aqueous suspensions.
- suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia ; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent.
- Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions.
- sterile fixed oils are conventionally employed as solvents or suspending media.
- any bland, fixed oil may be employed including synthetic mono- or diglycerides.
- fatty acids such as oleic acid can be used in the preparation of injectables.
- a composition of the invention may also be administered in the form of suppositories for rectal administration of the drug.
- These compositions can be prepared by mixing the drug with a suitable non -irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- suitable non -irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- Such materials are, for example, cocoa butter and polyethylene glycol.
- transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
- the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art (see, e.g., US Patent No. 5,023,252, issued June 1 1 , 1991 , incorporated herein by reference).
- patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
- Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art.
- a mechanical delivery device It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device.
- the construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art.
- Direct techniques for, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier.
- One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body is described in US Patent No. 5,01 1 ,472, issued April 30, 1991 .
- compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired.
- Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M.F. et al., "Compendium of Excipients for Parenteral Formulations” PDA Journal of Pharmaceutical Science & Technology 1998, 52(5 ), 238-31 1 ; Strickley, R.G “Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States ( 1999)-Part-1 " PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349 ; and Nema, S.
- compositions for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid) ; alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine) ; adsorbents (examples include but are not limited to powdered cellulose and activated charcoal) ; aerosol propellents (examples include but are not limited to carbon dioxide, CCl 2 F 2 , F2CIC-CCIF2 and CCIF3) air displacement agents (examples include but are not limited to nitrogen
- clarifying agents include but are not limited to bentonite
- emu lsifying agents include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate
- encapsulating agents include but are not limited to gelatin and cellulose acetate phthalate
- flavorants include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin
- humectants include but are not limited to glycerol, propylene glycol and sorbitol
- compositions according to the present invention can be illustrated as follows:
- Sterile IV Solution A 5 mg/mL solution of the desired compound of this invention can be made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1 - 2 mg/mL with sterile 5% dextrose and is administered as an IV infusion over about 60 minutes.
- Lyophilised powder for IV administration A steri le preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lyophilised powder, (ii) 32- 327 mg/mL sodium citrate, and (iii) 300 - 3000 mg Dextran 40.
- the formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/mL, which is further diluted with saline or dextrose 5% to 0.2 - 0.4 mg/mL, and is administered either IV bolus or by IV infusion over 15 - 60 minutes.
- Intramuscular suspension The following solution or suspension can be prepared, for intramuscular injection: 50 mg/mL of the desired, water-insoluble compound of this invention
- a large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 1 50 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.
- Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix. Tablets: A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.
- a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into
- Immediate Release Tablets/Capsules These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication.
- the active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques.
- the drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water.
- the com pounds of this invention can be admi nistered as the sole pha rmaceutica l agent or i n com bi nati on with one or m ore other pharmaceutical agents where the combination causes no unacceptable adverse effects.
- the present invention relates also to such combinations.
- the compounds of this invention can be combined with known anti-hyper- proliferative or other indication agents, and the like, as well as with admixtures and combinations thereof.
- Other indication agents include, but are not limited to, anti-angiogenic agents, mitotic inhibitors, alkylating agents, anti-metabolites, DNA-intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, toposisomerase inhibitors, biological response modifiers, or anti-hormones.
- the additional pharmaceutical agent can be aldesleukin, alendronic acid, alfaferone, a litreti noin , allopurinol, a loprim , aloxi , altretamine, aminoglutethimide, amifostine, amrubicin, amsacrine, anastrozole, anzmet, aranesp, arglabin, arsenic trioxide, aromasin, 5-azacytidine, azathioprine, BAY 80-6946, BCG or tice BCG, bestatin, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, broxuridine , bortezomib, busulfan, calcitonin, campath, capecitabine, carboplatin, casodex, cefesone, celmoleukin, cerubidine, chlorambucil, cisplatin, cladribine,
- a compound of general formula (I) as defined herein can optionally be administered in combination with one or more of the following: 1311-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin, alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin, amsacrine, anastrozole, arglabin, arsenic trioxide, asparaginase, azacitidine, basiliximab, BAY 80-6946, BAY 1000394, BAY 86-9766 (RDEA 119), belotecan, bendamustine, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, busulfan, cabazitaxel, calcium folinate, calcium levofolinate, capecitabine,
- Optional anti-hyper-proliferative agents which can be added to the composition include but are not limited to compounds listed on the cancer chemotherapy drug regimens in the 11 th Edition of the Merck Index, (1996), which is hereby incorporated by reference, such as asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycine), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone
- anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (Ninth Edition), editor Molinoff et al., publ.
- anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to other anti-cancer agents such as epothilone and its derivatives, irinotecan, raloxifen and topotecan.
- the compounds of the invention may also be administered in combination with protein therapeutics.
- protein therapeutics suitable for the treatment of cancer or other angiogenic disorders and for use with the compositions of the invention include, but are not limited to, an interferon (e.g., interferon .alpha., .beta., or .gamma.) supraagonistic monoclonal antibodies, Tuebingen, TRP-1 protein vaccine, Colostrinin, anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab, trastuzumab, denileukin diftitox, rituximab, thymosin alpha 1 , bevacizumab, mecasermin, mecasermin rinfabate, oprelvekin, natalizumab, rhMBL, MFE-CP1 + ZD-2767-P, ABT-828, ErbB2-specific immunotoxin, SGN-
- Monoclonal antibodies useful as the protein therapeutic include, but are not limited to, muromonab-CD3, abciximab, edrecolomab, daclizumab, gentuzumab, alemtuzumab, ibritumomab, cetuximab, bevicizumab, efalizumab, adalimumab, omalizumab, muromomab-CD3, rituximab, daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.
- a compound of general formula (I ) as defined herein can optionally be administered in combination with one or more of the following: ARRY-162, ARRY-300, ARRY-704, AS-703026, AZD-5363, AZD-8055, BEZ-235, BGT-226, BKM- 1 20 , BY L-719, CAL-101 , CC-223, CH-5132799, deforolimus, E-6201 , enzastaurin , GDC-0032, GDC-0068, GDC-0623, GDC-0941 , GDC-0973, GDC- 0980, GSK-2110183, GSK-2126458, GSK-2141795, MK-2206, novolimus, OSI-027, perifosine, PF-04691502, PF-05212384, PX-866, rapamycin, RG-7167, RO- 4987655, RO-5126766, selumetinib, TAK-733, tramet
- cytotoxic and/or cytostatic agents in combination with a compound or composition of the present invention will serve to:
- (6) provide for a longer survival time among treated patients compared to standard chemotherapy treatments, (7) provide a longer time for tumor progression, and/or (7) yield efficacy and tolerability results at least as good as those of the agents used alone, compared to known instances where other cancer agent combinations produce antagonistic effects.
- a compound of the present invention may be used to sensitize a cell to radiation. That is, treatment of a cell with a compound of the present invention prior to radiation treatment of the cell renders the cell more susceptible to DNA damage and cell death than the cell would be in the absence of any treatment with a compound of the invention.
- the cell is treated with at least one compound of the invention.
- the present invention also provides a method of killing a cell, wherein a cell is administered one or more compounds of the invention in combination with conventional radiation therapy.
- the present invention also provides a method of rendering a cell more susceptible to cell death, wherein the cell is treated one or more compounds of the invention prior to the treatment of the cell to cause or induce cell death.
- the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage for the purpose of inhibiting the function of the normal cell or killing the cell.
- a cell is killed by treating the cell with at least one DNA damaging agent. That is, after treating a cell with one or more compounds of the invention to sensitize the cell to cell death, the cell is treated with at least one DNA damaging agent to kill the cell.
- DNA damaging agents useful in the present invention include, but are not limited to, chemotherapeutic agents (e.g. , cisplati n um ) , ionizi ng radiation (X-rays, ultraviolet radiation ), carcinogenic agents, and mutagenic agents.
- a cell is killed by treating the cell with at least one method to cause or induce DNA damage.
- methods include, but are not limited to, activation of a cell signalling pathway that results in DNA damage when the pathway is activated, inhibiting of a cell signalling pathway that results in DNA damage when the pathway is inhibited, and inducing a biochemical change in a cell, wherein the change results in DNA damage.
- a DNA repair pathway in a cell can be inhibited, thereby preventing the repair of DNA damage and resulting in an abnormal accumulation of DNA damage in a cell.
- a compound of the invention is administered to a cell prior to the radiation or orther induction of DNA damage in the cell.
- a compound of the invention is administered to a cell concomitantly with the radiation or orther induction of DNA damage in the cell.
- a compound of the invention is administered to a cell immediately after radiation or orther induction of DNA damage in the cell has begun.
- the cell is in vitro. In another embodiment, the cell is in vivo.
- the compounds of the present invention have surprisingly been found to effectively inhibit allo-MEK and may therefore be used for the treatment or prophylaxis of diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by allo-MEK, such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g.
- leukaemias and myelodysplastic syndrome including leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
- the present invention covers a compound of general formula (I), or a stereoisomer, a tautomer, an N-oxide, a hyd rate, a solvate, or a sa lt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described and defined herein, for use in the treatment or prophylaxis of a disease, as mentioned supra.
- Another particular aspect of the present invention is therefore the use of a compound of general formula ( I ) described supra for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease.
- the diseases referred to in the two preceding paragraphs are diseases of uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases which are accompanied with uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly in which the uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses is mediated by Mps-1 , such as, for example, haematological tumours, solid tumours, and/or metastases thereof, e.g.
- leukaemias and myelodysplastic syndrome including leukaemias and myelodysplastic syndrome, malignant lymphomas, head and neck tumours including brain tumours and brain metastases, tumours of the thorax including non-small cell and small cell lung tumours, gastrointestinal tumours, endocrine tumours, mammary and other gynaecological tumours, urological tumours including renal, bladder and prostate tumours, skin tumours, and sarcomas, and/or metastases thereof.
- inappropriate within the context of the present invention, in particular in the context of "inappropriate cellular immune responses, or inappropriate cellular inflammatory responses", as used herein, is to be understood as preferably meaning a response which is less than, or greater than normal, and which is associated with, responsible for, or results in, the pathology of said diseases.
- the use is in the treatment or prophylaxis of diseases, wherein the diseases are haemotological tumours, solid tumours and/or metastases thereof.
- the diseases are haemotological tumours, solid tumours and/or metastases thereof.
- the present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat mammalian hyper- proliferative disorders.
- Compounds can be utilized to inhibit, block, reduce, decrease, etc., cell proliferation and/or cell division, and/or produce apoptosis.
- This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof ; etc. which is effective to treat the disorder.
- Hyper- proliferative disorders include but are not limited, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumors, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukemias. Examples of breast cancer include, but are not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, and lobular carcinoma in situ.
- cancers of the respiratory tract include, but are not limited to small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
- brain cancers include, but are not limited to brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumor.
- Tumors of the male reproductive organs include, but are not limited to prostate and testicular cancer.
- Tumors of the female reproductive organs include, but are not limited to endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus.
- Tumors of the digestive tract include, but are not limited to anal, colon, colorectal, esophageal, gallbladder, gastric, pancreatic, rectal, small- intestine, and salivary gland cancers.
- Tumors of the urinary tract include, but are not limited to bladder, penile, kidney, renal pelvis, ureter, urethral and human papillary renal cancers.
- Eye cancers include, but are not limited to intraocular melanoma and retinoblastoma.
- liver cancers include, but are not limited to hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.
- Skin cancers include, but are not limited to squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.
- Lymphomas include, but are not limited to AIDS- related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
- Sarcomas include, but are not limited to sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
- Leukemias include, but are not limited to acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
- treating or “treatment” as stated throughout this document is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a carcinoma.
- the present invention also provides methods for the treatment of disorders associated with aberrant mitogen extracellular kinase activity, including, but not limited to stroke, heart failure, hepatomegaly, cardiomegaly, diabetes, Alzheimer's disease, cystic fibrosis, symptoms of xenograft rejections, septic shock or asthma.
- Effective amounts of compounds of the present invention can be used to treat such disorders, including those diseases (e.g. , cancer) mentioned in the Background section above. Nonetheless, such cancers and other diseases can be treated with compounds of the present invention , regard less of the mechanism of action and/or the relationship between the kinase and the disorder.
- aberrant kinase activity or "aberrant tyrosine kinase activity, " includes any abnormal expression or activity of the gene encoding the kinase or of the polypeptide it encodes. Examples of such aberrant activity, include, but are not limited to, over-expression of the gene or polypeptide ; gene amplification ; mutations which produce constitutively-active or hyperactive kinase activity ; gene mutations, deletions, substitutions, additions, etc.
- the present invention also provides for methods of inhibiting a kinase activity, especially of mitogen extracellular kinase, comprising administering an effective amount of a compound of the present invention, including salts, polymorphs, metabolites, hydrates, solvates, prodrugs (e.g. : esters) thereof, and diastereoisomeric forms thereof.
- Kinase activity can be inhibited in cells (e.g. , in vitro), or in the cells of a mammalian subject, especially a human patient in need of treatment.
- the present invention also provides methods of treating disorders and diseases associated with excessive and/or abnormal angiogenesis.
- Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism.
- a number of pathological conditions are associated with the growth of extraneous blood vessels. These include, e. g . , diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity [Aiello et al. New Engl. J. Med. 1994, 331 , 1480 ; Peer et al. Lab. Invest. 1995, 72, 638] , age-related macular degeneration [AMD ; see , Lopez et a l . I nvest . Opththalmol. Vis. Sci.
- neovascular glaucoma neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc.
- RA rheumatoid arthritis
- the increased blood supply associated with cancerous and neoplastic tissue encourages growth, leading to rapid tumor enlargement and metastasis.
- the growth of new blood and lymph vessels in a tumor provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer.
- compounds of the present invention can be utilized to treat and/or prevent any of the aforementioned angiogenesis disorders, e.g. , by inhibiting and/or reducing blood vessel formation ; by inhibiting, blocking, reducing, decreasing, etc. endothelial cell proliferation or other types involved in angiogenesis, as well as causing cell death or apop
- the effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication.
- the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
- the total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 20 mg/kg body weight per day.
- Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing.
- "drug holidays" in which a patient is not dosed with a drug for a certain period of time may be beneficial to the overall balance between pharmacological effect and tolerability.
- a unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day.
- the average daily dosage for administration by injection will preferably be from 0.01 to 200 mg/kg of total body weight.
- the average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
- the average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
- the average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
- the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
- the average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
- the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like.
- the desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.
- the diseases of said method are haematological tumours, solid tumour and/or metastases thereof.
- the compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of tumour growth and metastases, especially in solid tumours of all indications and stages with or without pre-treatment of the tumour growth.
- BIOLOGICAL EVALUATION The utility of the compounds of the present invention can be illustrated, for example, by their activity in vitro in the in vitro tumor cell proliferation assay described below.
- the link between activity in tumor cell proliferation assays in vitro and anti-tumor activity in the clinical setting has been very well established in the art.
- taxol Silvestrini et al., 1993
- taxotere Bissery et al., 1995
- topoisomerase inhibitors Edelman & Gandara, 1996) were demonstrated with the use of in vitro tumor proliferation assays.
- Demonstration of the activity of the compounds of the present invention may be accomplished through in vitro, ex vivo, and in vivo assays that are well known in the art. For example, to demonstrate the activity of the compounds of the present invention, the following assays may be used.
- the average value also referred to as the arithmetic mean value
- the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.
- Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch.
- PI3Ka inhibitory activity of compounds of the present invention was quantified employing the HTRF-based PI3K inhibition assay as described below.
- the PI3-Kinase HTRF Assay kit from Millipore (# 33-017) was used. With this kit the phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) generated in the kinase reaction is detected by displacement of a biotinylated ligand from an energy transfer complex consisting of a Europium-labeled anti-GST monoclonal antibody, a GST-tagged PH domain, biotinylated PIP 3 and Streptavidin-Allophycocyanin (APC).
- PIP 3 phosphatidylinositol 3,4,5-trisphosphate
- ATP adenosine triphosphate
- reaction was stopped by the addition of 1 ⁇ _ of an stop solution (containing the biotinylated PIP 3 used as a tracer), then 1 ⁇ _ detection mix (containing a Europium- labeled anti-GST monoclonal antibody, a GST-tagged PH domain, and Streptavidin- Allophycocyanin) was added and resulting mixture was incubated 3 h at 22 °C to allow the formation of complexes between the detection reagents and either the PIP 3 generated in the kinase reaction, or the biotinylated PIP 3 added with the stop solution.
- an stop solution containing the biotinylated PIP 3 used as a tracer
- 1 ⁇ _ detection mix containing a Europium- labeled anti-GST monoclonal antibody, a GST-tagged PH domain, and Streptavidin- Allophycocyanin
- the amount of energy transfer complex consisting of a Europium-labeled anti-GST monoclonal antibody, a GST-tagged PH domain, biotinylated PIP 3 and Streptavidin-Allophycocyanin (APC) was evaluated by measurement of the resonance energy transfer from the Europium-labeled anti-GST monoclonal antibody to the Streptavidin-Allophycocyanin. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm were measured using a TR-FRET reader, e.g. , a Pherastar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer).
- TR-FRET reader e.g. , a Pherastar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer).
- the ratio of the emissions at 665 nm and at 622 nm was taken as the measure for the amount of biotinylated PIP 3 bound to the GST-tagged PH domain, which is negatively correlated with the amount of PIP 3 generated.
- test compounds were tested on the same microtiter plate at 10 different concentrations in the range of 25 ⁇ to 1 .3 nM (25 ⁇ , 8.3 ⁇ , 2.8 ⁇ , 0.93 ⁇ , 0.31 ⁇ , 103 ⁇ , 34 ⁇ , 1 1 ⁇ , 3.8 nM and 1.3 nM , a dilution series prepared before the assay at the level of the 80-fold cone, stock solutions by serial 1 :3 dilutions) in duplicate values for each concentration and IC 50 values were calculated by a 4-parameter fit using in-house software.
- the following example compounds displayed an average IC 50 in the PI 3K alpha biochemical assay of less than 10 nanomolar: 1 , 5, 6, 8, 9, 10, 12, 14, 17, 18, 19, 20, 21 , 23, 25, 27, 28, 29, 30, 32, 34, 35, 36, 37, 38, 39, 41 .
- the following example compounds displayed an average IC 50 in the PI3K alpha biochemical assay of between 10 and 50 nanomolar: 2, 3, 4, 7, 11 , 16, 24.
- the following example compound displayed an average IC 50 in the PI3K alpha biochemical assay of greater than 50 nanomolar: 40. Percent inhibition values obtained for example compounds at a 0.93 ⁇ concentration are given in Table 1.
- ⁇ 3 ⁇ inhibitory activity of compounds of the present invention was quantified employing the HTRF based PI3K inhibition assay as described below.
- the PI3-Kinase HTRF Assay kit from Millipore (# 33-017) was used. With this kit the phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) generated in the kinase reaction is detected by displacement of a biotinylated ligand from an energy transfer complex consisting of a Europium-labeled anti-GST monoclonal antibody, a GST-tagged PH domain, biotinylated PIP 3 and Streptavidin-Allophycocyanin (APC).
- PIP 3 phosphatidylinositol 3,4,5-trisphosphate
- PIP 2 phosphatidylinositol-4,5- bisphosphate
- ATP adenosine triphosphate
- the reaction was stopped by the addition of 1 ⁇ _ of an stop solution (containing the biotinylated PIP 3 used as a tracer). Then 1 ⁇ _ detection mix (containing a Europium- labeled anti-GST monoclonal antibody, a GST-tagged PH domain, and Streptavidin- Allophycocyanin) was added and resulting mixture was incubated for 3 h at 22 °C to allow the formation of complexes between the detection reagents and either the PIP 3 generated in the kinase reaction, or the biotinylated PIP 3 added with the stop solution.
- an stop solution containing the biotinylated PIP 3 used as a tracer.
- the amount of energy transfer complex consisting of a Europium-labeled anti-GST monoclonal antibody, a GST-tagged PH domain, biotinylated PIP 3 and Streptavidin-Allophycocyanin (APC) was evaluated by measurement of the resonance energy transfer from the Europium-labeled anti-GST monoclonal antibody to the Streptavidin-Allophycocyanin. Therefore, the fluorescence emissions at 620 nm and 665 nm after excitation at 350 nm were measured using a TR-FRET reader, e.g. , a Pherastar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer).
- TR-FRET reader e.g. , a Pherastar (BMG Labtechnologies, Offenburg, Germany) or a Viewlux (Perkin-Elmer).
- the ratio of the emissions at 665 nm and at 622 nm were taken as the measure for the amount of biotinylated PIP 3 bound to the GST-tagged PH domain, which is negatively correlated with the amount of PIP 3 generated.
- test compounds were tested on the same microtiter plate at 10 different concentrations in the range of 25 ⁇ to 1 .3 nM (25 ⁇ , 8.3 ⁇ , 2.8 ⁇ , 0.93 ⁇ , 0.31 ⁇ , 103 ⁇ , 34 ⁇ , 1 1 ⁇ , 3.8 nM and 1.3 nM , a dilution series prepared before the assay at the level of the 80-fold cone, stock solutions by serial 1 :3 dilutions) in duplicate values for each concentration and IC 50 values were calculated by a 4 parameter fit using in-house software.
- the following example compounds displayed an average IC 50 i n the PI 3K beta biochemical assay of less than 10 nanomolar: 25, 28, 29, 38 and 39.
- the following example compounds displayed an average IC 50 in the PI3K beta biochemical assay of between 10 and 50 nanomolar: 2, 5, 8, 9, 10, 1 1 , 12, 14, 16, 17, 18, 19, 20, 21 , 23, 24, 27, 30, 32, 34, 35, 36, 37 and 41 .
- the following example compounds displayed an average IC 50 in the PI3K beta biochemical assay of greater than 50 nanomolar: 1 , 3, 4, 6, 7, and 40.
- Percent inhibition values obtained for example compounds at a 0.93 ⁇ concentration are given in Table 1. Table 1
- Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders.
- the PIK3CA gene is mutated with high frequency in human breast cancers.
- Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor.
- D.-S. Cho, K.; Ryu, B.-K.; Lee, M.-G.; Park, J.-l.; Chae, K.-S.; Kim, H.-J.; Chi, S.- G. Int. J. Cancer 2003, 704, 318-327. Frequent monoallelic deletion of PTEN and its reciprocal association with PIK3CA amplification in gastric carcinoma.
- the PI3K pathway as an integrator of multiple inputs during tumorigenesis.
- Angiopoietin-1 modulates endothelial cell function and gene expression via the transcription factor FKHR (FOX01).
- Glycogen synthase kinase-3b regulates cyclin D1 proteolysis and subcellular localization.
- Akt2 negatively regulates assembly of the POSH-MLK-JNK signaling complex.
- PTEN/MMAC Protein kinase B
- Phosphoinositide-dependent Kinase-2 is a distinct protein kinase enriched in a novel cytoskeletal fraction associated with adipocyte plasma membranes.
- Akt Akt phosphorylates and negatively regulates apoptosis signal-regulating kinase 1.
- Phosphatidylinositol 3'-Kinase Activation Leads to Multidrug Resistance Protein-1 Expression and Subsequent Chemoresistance in Advanced Prostate Cancer Cells.
- PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas.
- Transdifferentiated retinal pigment epithelial cells are immunoreactive for vascular endothelial growth factor in surgically excised age-related macular degeneration-related choroidal neovascular membranes.
- PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy.
- MDM2 master regulator of the p53 tumor suppressor protein.
- Akt enhances Mdm2-mediated ubiquitination and degradation of p53.
- PI3K-Akt pathway Its functions and alterations in human cancer.
- Tumor necrosis factor induces phosphorylation and translocation of BAD through a phosphatidylinositide-3-OH kinase-dependent pathway.
- phosphatidylinositol 3'-kinase p85a gene is an oncogene in human ovarian and colon tumors.
- Wortmannin a potent and selective inhibitor of phosphatidylinositol-3-kinase.
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AP2013006921A AP3337A (en) | 2010-11-11 | 2011-11-08 | Aminoalcohol substituted 2,3-dihydroimidazo[1,2-C]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis |
NZ610018A NZ610018A (en) | 2010-11-11 | 2011-11-08 | Aminoalcohol substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis |
MX2013005305A MX2013005305A (es) | 2010-11-11 | 2011-11-08 | Derivados de 2,3-dihidroimidazo[1,2-c]quinazolina sustituidos con aminoalcoholes que son de utilidad para tratar trastornos hiperproliferativos y enfermedades asociadas a la angiogenesis. |
US13/885,122 US8895549B2 (en) | 2010-11-11 | 2011-11-08 | Aminoalcohol substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis |
EA201300556A EA024406B1 (ru) | 2010-11-11 | 2011-11-08 | АМИНОСПИРТ-ЗАМЕЩЕННЫЕ ПРОИЗВОДНЫЕ 2,3-ДИГИДРОИМИДАЗО[1,2-с]ХИНАЗОЛИНА, ПРИГОДНЫЕ ДЛЯ ЛЕЧЕНИЯ ГИПЕРПРОЛИФЕРАТИВНЫХ НАРУШЕНИЙ И ЗАБОЛЕВАНИЙ, СВЯЗАННЫХ С АНГИОГЕНЕЗОМ |
AU2011328192A AU2011328192B2 (en) | 2010-11-11 | 2011-11-08 | Aminoalcohol substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis |
JP2013538163A JP6196156B2 (ja) | 2010-11-11 | 2011-11-08 | 過剰増殖性障害および血管新生に関連する疾患の治療のために有用なアミノアルコール置換2,3−ジヒドロイミダゾ[1,2−c]キナゾリン誘導体 |
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EP11784978.6A EP2638045B1 (de) | 2010-11-11 | 2011-11-08 | Aminoalkoholsubstituierte 2,3-dihydroimidazo-[1,2-c]-chinazolinderivate zur behandlung von hyperproliferativen störungen und erkrankungen im zusammmenhang mit angiogenese |
CN201180023122.7A CN102906094B (zh) | 2010-11-11 | 2011-11-08 | 用于治疗过度增殖性病症和与血管发生相关的疾病的氨基醇取代的2,3-二氢咪唑并[1,2-c]喹唑啉衍生物 |
SG2013033634A SG190100A1 (en) | 2010-11-11 | 2011-11-08 | Aminoalcohol substituted 2,3-dihydroimidazo[1,2-c]quinazoline derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis |
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BR112013011634A BR112013011634A2 (pt) | 2010-11-11 | 2011-11-08 | derivados de 2,3-di-hidroimidazol[1,2-c]quinazolina substituídos por aminoálcool úteis para tratar os distúrbios hiperproliferativos e as doenças associadas com a angiogênese derivados de 2,3-di-hidroimidazol[1,2-c] |
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MA35889A MA34655B1 (fr) | 2010-11-11 | 2013-05-09 | Dérivés de 2,3- dihydroimidazo[1,2-c]quinazoléine substitués par un aminoalcool utiles pour traiter des troubles hyperprolifératifs et des maladies associées à l'angiogenèse |
CR20130213A CR20130213A (es) | 2010-11-11 | 2013-05-10 | Derivados de 2,3-dihidroimidazo[1,2-c]quinazolina sustituidos con aminoalcoholes que son de utilidad para tratar trastornos hiperproliferativos y enfermedades asociadas a la angiogènesis |
CU2013000069A CU20130069A7 (es) | 2010-11-11 | 2013-05-10 | Derivados de 2,3-dihidroimidazo[1,2-c] quinazolina sustituidos con aminoalcoholes que son de utilidad para tratar trastornos hiperproliferativos y enfermeddes asociadas a la angiogénesis |
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